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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2776.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Effects of Hypercholesterolemia on Myocardial Ischemia-Reperfusion Injury in LDL Receptor–Deficient Mice

Wesley G. Girod; Steven P. Jones; Nola Sieber; Tak Yee Aw; David J. Lefer

From the Department of Molecular and Cellular Physiology (S.P.J., N.S., T.Y.A., D.J.L.) and the Department of Surgery (W.G.G.), LSU Medical Center, Shreveport, La.

Correspondence and reprint requests to David J. Lefer, PhD, Department of Molecular and Cellular Physiology, LSU Medical Center, 1501 Kings Highway, Shreveport, LA 71130. E-mail dlefer{at}lsumc.edu

Abstract—Hypercholesterolemia is a primary risk factor for atherosclerosis, coronary artery disease, and myocardial infarction. We subjected low density lipoprotein receptor–deficient (LDLr –/–) and control (wild-type) mice to 30 minutes of myocardial ischemia and 120 minutes of reperfusion. Myocardial infarction per area at risk (AAR) was noted under baseline conditions to be significantly (P<0.05) smaller in the LDLr –/– mice compared with wild-type mice (24.7±3.2% and 38.8±4.3% of AAR, respectively). Subsequently, mice were fed a high-cholesterol diet (HCD) for 2 or 12 weeks, which resulted in significant increases in serum cholesterol levels in both LDLr –/– and wild-type groups. After 2 weeks of the HCD, the LDLr –/– mice demonstrated a significant elevation (P<0.01) in myocardial necrosis per AAR (50.2±5.36% of AAR) compared with the normal-diet LDLr –/– group, whereas the short-term HCD-fed wild-type mice demonstrated no significant difference from baseline. In contrast, wild-type mice fed the HCD for 12 weeks revealed a significant (P<0.05) decrease in necrosis per AAR, which was 22.5±3.2% of the AAR in comparison with that in the normal-diet wild-type mice (38.8±4.3% of AAR). LDLr –/– mice on the same long-term HCD showed a similar significantly (P<0.05) decreased infarct size, which was 13.2±4.0% of the AAR. In additional experiments, we determined that myocardial tissue total glutathione (GSH) levels were reduced after 2 weeks of the HCD and were significantly increased after 12 weeks of the HCD in the LDLr –/– mouse heart. These data suggest that short-term cholesterol feeding renders the myocardium of LDLr –/– mice more susceptible to ischemia-reperfusion injury, whereas more long-term hypercholesterolemia confers cardioprotection in the LDLr –/– mouse heart.

Key Words: infarct • cholesterol • neutrophils • mutant mice

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